ADP-ribosyl cyclase (ADPR-cyclase) is widely distributed and plays a critical role in regulation of intracellular Ca2+ concentration ([Ca2+]i) via cyclic ADP-ribose (cADPR) production [Guse et al., Nature 1999(398):70-3; Galione et al., Sci STKE 2000(41):PE1; Lee, Curr. Mol. Med. 2004(4): 227-37]. The metabolite cADPR is known to increase [Ca2+]i by releasing from intracellular Ca2+ stores or by Ca2+ influx through plasma membrane Ca2+ channels from plants to mammals [Guse et al., Nature 1999(398):70-3; Galione et al., Sci STKE 2000(41):PE1; Lee, Annu. Rev. Pharmacol Toxicol. 2001(41):317-45; Partida-Sanchez et al., Nat. Med. 2001(7): 1209-16].
The homeostasis of intracellular Ca2+ ([Ca2+]i) is essential for regulate of physiological functions. Moreover, calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different intracellular actions, ranging from contraction to secretion, from proliferation or hypertrophy to cell death. The abnormal increase of [Ca2+]i causes physiologic or pathophysiologic disorders, such as hypertension, hypertensive diabetes, obesity, ischemia, and renal dysfunction et al., [Resnick et al., Am. J. Hypertens. 1993(6): 123-34].
Angiotensin II (Ang II) plays a key role in the regulation of cardiovascular homeostasis. Acting on both the “content” and the “container” Ang II regulates blood volume and vascular resistance. The wide spectrum of Ang II target tissues includes the adrenals, kidney, brain, pituitary gland, vascular smooth muscle, and the sympathetic nervous system. Angiotensin is not only a blood-borne hormone that is produced and acts in the circulation but is also formed in many tissues such as brain, kidney, heart, and blood vessels [Gasparo et al., Pharmacol. Rev. 2000(52):415-72]. Recent studies report that Ang II induces ADPR-cyclase activation and production of cADPR [Fellner et al., Am. J. Physiol Renal Physiol. 2005(288): F785-91; Higashida et al., Biochem. J. (2000)352:197-202].
ADPR-cyclase is present in brain, heart, kidney, arterial smooth muscle cells, and bone marrow cells [Hirata et al., FEBS Lett. (1994)356:244-8; de Toledo et al., Circ. Res. (2000)86:1153-9; Ceni et al., J. Biol. Chem. (2003)278:40670-8; Zielinska et al., Life Sci. (2004)74:1781-90; Xie et al., Biochem. Biophys. Res. Commun. (2005)330:1290-8]. A number of studies indicate that ADPR-cyclase/CD38 is necessary for Ca2+ sensitive biologic responses in which insulin secretion, obesity, neurodegeneration [Panfoli et al. Invest. Ophthalmol. Vis. Sci. (2007)48:978-84; Maria et al., FASEB J. (2007)21:3629-39; Duo et al., Nature (2007)446:41-5].
A study with mice disrupted CD38 gene has demonstrated that formation of cADPR is not reduced greatly in mouse kidney, brain, and heart [Partida-Sanchez et al., Nat. Med. 2001(7): 1209-16], suggesting that ADPR-cyclases other than CD38 exist. However, the ADPR-cyclase(s) present in these tissues has not been cloned, and the cADPR antagonistic derivatives such as 8-Br-cADPR and 8-NH2-cADPR do not distinguish the Ca2+ signals induced by the unidentified ADPR-cyclase or CD38 [Walseth et al., Biochim. Biophys. Acta. (1993)1178:235-42].
The present invention provides available bisphenyl derivatives that inhibit specific ADPR-cyclase activity with high potency, but not CD38. These compounds that are thought to contribute to the prevention or treatment of various diseases, including hypertension and diabetic nephropathy.